Diagnosis, evaluation and treatment of coronary artery disease by exercise simulation using closed loop drug delivery of an exercise simulating agent beta agonist

ABSTRACT

Methods and devices for the diagnosis, evaluation and treatment of coronary artery disease (CAD) by means of a closed-loop drug delivery system that delivers an exercise simulating agent, including novel exercise simulating agents which elicit both acute and adaptive cardiovascular responses similar to those elicited by aerobic activity are provided. The acute responses to the exercise simulating agent are used to diagnose and evaluate CAD in lieu of the acute responses to aerobic exercise. Due to their adaptive responses these compounds may be used to treat CAD in lieu of the adaptive responses caused by aerobic exercise training or to treat other conditions where the adaptive responses caused by aerobic exercise are desirable.

This is a divisional of co-pending application Ser. No. 308,683 filed onFeb. 9, 1989 U.S. Pat. No. 5,108,363 which is a continuation-in-part ofSer. No. 157,875 filed on Feb. 19, 1988.

FIELD OF THE INVENTION

The invention relates generally to the diagnosis, evaluation andtreatment of coronary artery disease and more specifically to a systemfor closed loop delivery of a exercise simulating agent, said exercisesimulating agent eliciting both acute and adaptive cardiovascularresponses similar to those resulting from aerobic activity. The presentinvention is also directed to novel exercise stimulating agents and totherapeutic agents having both acute and adaptive cardiovascular andmetabolic effects.

BACKGROUND AND INTRODUCTION TO THE INVENTION

Publications and other reference materials referred herein areincorporated herein by reference and are numerically referenced in thefollowing text and respectively grouped in the appended Bibliographywhich immediately precedes the claims.

The drugs described and claimed herein that elicit acute and adaptivecardiovascular responses similar to the types of responses elicited byaerobic activity are referred to as Exercise Simulating Agent BetaAgonists (hereinafter "exercise simulating agents" or "ESA™ betaagonists") for the purposes of disease including CAD, aortic aneurysm,peripheral vascular disease and stroke. In the majority of cases, thefirst indication of atherosclerosis is seen during exercise when theoxygen requirement of the heart muscle (myocardium) increases.

Indeed, atherosclerosis is generally silent until it manifests itself asCAD, peripheral vascular disease, stroke, or sudden death. There areessentially no easy, rapid or economic tests to detect the presence ofatherosclerosis before it is clinically evident, and the only treatmentfor it is the modification of risk factors (i.e., cigarette smoking,high blood pressure, blood cholesterol and diabetes) onceatherosclerosis is detected in an asymptomatic individual.

Disorders of the coronary arteries are common manifestations ofatherosclerosis. CAD develops when the coronary circulation isinsufficient to supply the oxygen requirements of the heart muscle,resulting in ischemia. CAD has three major clinical manifestations:angina pectoris, a condition marked by periodic episodes of chest pain,especially during exertion, that result from transient and reversiblemyocardial ischemia (when CAD has progressed such that it is clinicallyapparent, it is also referred to as ischemic heart disease); myocardialinfarction, the term used to describe acute necrotic changes in themyocardium that are usually secondary to coronary occlusion (heartattacks); and sudden death, an unexpected cardiac death occurring withinan hour of the onset of the heart attack, often without symptoms CAD isclearly a diagnostic challenge to the practicing physician because it isoften silent and because of the severe consequences of its clinicalcourse. this invention. While eliciting such cardiovascular responses,it has been discovered that the effects of administration of ESA™ betaagonists can be finely controlled so that the heart is exercised orstressed at selected levels without body motion.

According to the American Heart Association, heart disease, stroke andrelated disorders accounted for nearly one million deaths in 1984,almost as many deaths as from all other causes of deaths combined.Cardiovascular and cerebrovascular diseases affect over 63 millionpeople in the United States, equivalent to one of every four Americans.Approximately 5 million people in the United States suffer from coronaryartery disease (hereinafter "CAD"), resulting in over 1.5 million heartattacks yearly, of which 550,000 are fatal. The annual economic cost ofcardiovascular disease alone is estimated to be $85 billion.Cardiovascular disease has many manifestations, of course, includingatherosclerosis.

Atherosclerosis is the most common form of arteriosclerosis, commonlyreferred to as "hardening of the arteries." Atherosclerosis is adegenerative process that narrows or blocks arteries in the heart, brainand other parts of the body; the interior walls of the arteries becomelined with deposits of fat, cholesterol, fibrin, cellular waste productsand calcium. These deposits form a rough, thick surface inside the bloodvessels, and interfere with both the smooth flow of blood and the amountof blood carried through the arteries. This narrowing of the bloodvessels restricts blood flow, causing ischemia (deficiency of blood dueto either functional constrictions or obstruction of a blood vessel),and is the underlying pathologic condition in many forms ofcardiovascular

Several developments in the diagnosis of CAD have taken place in thepast 15 or so years. Prior to 1970, the principal techniques availablefor the evaluation of the patient with heart disease were the clinicalexamination, the chest x-ray, and electrocardiography (hereinafter"ECG"). If these various modalities were inadequate and clinicalsymptoms were present, patients were often and in many cases still aresubjected to the invasive techniques of cardiac catherization, selectiveangiography, or both, with the resultant discomfort, risk and necessityfor hospitalization. Patients who were diagnosed with CAD usuallyreceived clinical examination supplemented by the relatively inaccuratechest x-ray and ECG. The introduction of other noninvasive techniquessuch as ECG coupled with an exercise stress test ("EST"), ambulatorymonitoring electrocardiography and various forms of radionuclideimaging, have improved the diagnosis and management of heart disease,but these techniques are not without serious drawbacks. The value of thenoninvasive techniques are limited by the selection of the appropriatediagnostic procedure or procedures, the skill and expertise of theindividual(s) performing the procedure, the ability of the patient tosuccessfully tolerate and complete the test, the proper interpretationof the results and the cost and availability of specialized equipment

Of the above-mentioned noninvasive techniques, exercise stress testingwith electrocardiography monitoring is one of the most commonly usedtests in the diagnosis of CAD in the United States. Clinical experiencehas repeatedly confirmed the value of EST in the diagnosis ofsymptomatic cardiac conditions which are not present at rest but ispresent under conditions of rate. A large group of patients in thetarget group are physically unable to exercise at all, or are unable toachieve a maximal test due to problems such as arthritis, limbabnormalities, obesity and other conditions. Other problems are relatedto the use of this technique, including the fact that exercise stresstesting is inconvenient to both patient and doctor. A maximal stresstest exhausts most patients and involves a significant recovery time.Additionally, maximal stress tests involve a degree of risk for thepatient of falling which is directly related to the use of a treadmill.Because of the physical movement associated with the exercise, placementof the electrodes is also a problem. Specially designed electrodes whichminimize motion artifacts, must be securely attached. Placing theelectrodes can involve shaving of the chest in man, and sometimesburnishing of the skin to achieve appropriate electrode contact. Takenas a whole, those necessities make exercise stress testing aninconvenient test for both patient and physician. Because of itsinherent difficulty, lack of sensitivity, lack of specificity, and cost,exercise stress testing is not generally recommended for asymptomaticindividuals (1).

Diagnosis of CAD by methods which can stress the heart in a manner thatmimics aerobic activity, while not forcing the patient to engage in suchstrenuous activities would vitiate many of the problems associated withdiagnosis of CAD by means of exercise stress testing. In fact, a testwherein the heart is stressed without the need for physical exercisewould be not only of great practicality, but would also allow for thetesting of those individuals who heretofore have been unable to engagein exercise stress testing. cardiac stress. At rest the heart mayperform adequately and meet the body's requirements for oxygen and othernutrients, but when the heart is stressed with exercise, CAD is morereadily detected. The cardiac changes elicited by stress include (1)increased heart rate; (2) increased cardiac output; (3) increased strokevolume due to increased venous return and increased myocardialcontractility; and (4) rise in systolic blood pressure. These changesincrease the heart's need for oxygen, and therefore increase the needfor coronary blood flow, creating a diagnostically revealing responsefor detection of CAD.

Exercise stress testing is performed after a baseline resting ECG istaken. The patient is then closely monitored through a protocol ofsequential levels of exercise. The Bruce protocol is the most commonprotocol used in the United States. This protocol specifies the speedand level of the incline of a motor driven treadmill during a total ofseven three-minute exercise states with no rest periods. The test isstopped when any of the following occur: when the protocol is completed;when the patient reaches a pre-set heart rate goal; when the patientexperiences acute discomfort; when a diagnostic change occurs in the EGGor blood pressure; or when the patient fatigues.

Despite the fact that exercise stress testing is an important method forthe diagnosis of CAD, there are drawbacks which limit its overall usage.A significant problem with the procedure is that exercise must bemaximal in order to obtain the greatest sensitivity. In other words, fora test to be considered diagnostically revealing, either the patientmust reach a level of stress that causes ischemia, or the patient mustcomplete the protocol by reaching a predetermined maximal heart

Several groups have described the intravenous infusion of syntheticcatecholamines (2, 3, 4, 5). U.S. Pat. No. 3,987,200 entitled "Methodfor Increasing Cardiac Contractility" issued to Tuttle et al. on Oct.19, 1976, discloses the synthetic catecholamine dobutamine. Dobutamineelicits certain specific cardiac responses without the adverse sideeffects that would accompany administration of a natural catecholamine.Dobutamine exerts a positive inotropic effect (increasing heartcontractility) without inducing arrhythmia and with minimal heart rateand blood pressure effects. When infused intravenously at high doses,dobutamine elicits increases in heart rate, myocardial contractility,arterial blood pressure, and coronary and skeletal muscle blood flow.Such responses resemble the effects of physical exercise. Although heartrate does increase with infusion of dobutamine, the drug was designed tospecifically minimize this effect. Increasing heart rate is referred toa positive chronotropic effect.

Since the development of dobutamine, there have been reports in thescientific literature on the relationship of dobutamine and physicaltraining (6). Results from studies utilizing dobutamine in the diagnosisof CAD (7, 8, 9) indicate that dobutamine infusion may be a reasonable,well-tolerated cardiovascular stress test used with the variousdiagnostic modalities. Use of dobutamine as an ESA™ beta agonist foradaptive response purposes has also been reported (10, 11, 12, 13, 14,15). However, and despite the fact that dobutamine elicits thecardiovascular responses normally associated with exercise, the use ofdobutamine has been limited because the drug must be intravenouslyinfused due to its relatively low potency, thus creating additional timeand complications for both patient and physician.

Dobutamine has also been administered to prevent bedrest inducedphysical deconditioning, and it was reported that infusions ofdobutamine could maintain or increase many of the physiologicexpressions associated with physical conditioning. (16). The use ofportable infusion pumps for the administration of dobutamine raised thepossibility of overcoming the necessity for hospital confinement,allowing for somewhat ambulatory movement (17, 18, 19, 20). Use of sucha system in an outpatient setting for general diagnosis and treatmentpurposes is of course negated by the need for an attached catheter tothe patient. The need for oral inotropic agents to replace this form oftherapy has been noted (17, 19). An oral agent, however, while perhapspotentially useful for therapeutic application would not be usefuldiagnostically, due to the need for fine control of the cardiac responseof the drug. For diagnostic purposes, it would be desirable to be ableto obtain specific cardiac response over a defined period of time, andto be able to reverse or reduce the effect simply and rapidly.

An orally effective compound, "KM-13", obtained from a specificalteration of dobutamine's chemical structure was recently discussed(21) and is the subject of a United States patent (22). The compoundproduces acute adrenergic cardiovascular responses which are similar tothose of dobutamine, but unlike dobutamine, KM-13 is more potent and iseffective when administered orally. Several synthetic compounds havinguses relating to the cardiovascular system and which can be orallyfulfilled by the device and the chemical agent used, each of which ismet by the invention described and claimed herein: (1) similarity ofresponse to that of exercise-induced stress (the ESA™ beta agonist mustelicit cardiovascular responses that mimic the diagnostically revealingresponses caused by aerobic exercise); (2) quick onset and cessation ofresponse (as with exercise, the temporal relationship of the heart'sresponse to the ESA™ beta agonist must be a close one); (3) dose relatedresponse (as with exercise, the response of the heart to an ESA™ betaagonist must be dose-related such that an increase in the dosage of anESA™ beta agonist must produce a related increase in the heart'sresponse); (4) safety (the heart's response to an ESA™ beta agonist mustbe as safe as is the response to exercise); and (5) convenience (theremust be a convenient and noninvasive means of delivering the ESA™ betaagonist into the patient). ESA™ beta agonists with beta-1 adrenergicactivity are presently preferred, while compounds with beta-2 adrenergicactivity can also be useful.

SUMMARY OF THE INVENTION

The present invention is directed to a method of eliciting in a mammalimmediate physical responses similar to those physical responseselicited by aerobic activity which comprises administering an exercisesimulating agent by a closed-loop drug delivery system. Preferred areexercise simulating agents ("ESA™ beta agonists") having the generalchemical structure: administered were known prior to the disclosure ofKM-13 (23, 24, 25, 26).

Because KM-13 is an ionic compound, delivery of the drug by othernoninvasive techniques is possible. It has recently been reported thatKM-13 can be administered to dogs utilizing an iontophoretic deliverysystem (27). However, while more potent than dobutamine, KM-13 is notsufficiently potent to be administered to humans iontophoretically,since the current required to deliver an effective dose would causeadverse effects such as skin burns.

Transdermal iontophoresis is a non-invasive technique in which anelectrical current is applied to the skin through two electrodes,whereby an ionized drug contained in one of the electrodes moves intothe body through the stratum corneum (e.g., skin) in response to thepotential across the electrodes. Such a delivery system allows forregulation of the amount of drug absorbed in the bloodstream through theskin as a function of the magnitude of the current applied. Because thesystem is non-invasive, both trauma and risk of infection are minimized;the later factor has increasing desirability due to the fears generatedby the risk of diseases from subcutaneous injections, e.g. AIDS.Transdermal iontophoretic devices have been marketed for several yearsand are approved by the Food and Drug Administration for use indelivering certain drugs (28). Recently, it has been reported that thebeta blocker metoprolol can be delivered iontophoretically (29).

In order for an ESA™ beta agonist system for inducing cardiac stress tobe medically practical in both clinical and outpatient settings, thereare five criteria that must be bloodstream of said mammal so that apredetermined range of cardiovascular responses is obtained; (c)monitoring the range of responses of said mammal; and (d) changinginfusion of said exercise simulating agent as required to maintain saidrange of responses. Suitable ESA™ beta agonists include compounds offormula I. Preferred ESA™ beta agonists include compounds of StructureII.

According to the above described method of the present invention, in oneaspect there is provided a method of simulating the cardiovascularresponses of a mammal to an exercise stress test ("ESA™ beta agonisttest") wherein the heart of said mammal is exercised or stressed at aselected level without body motion which comprises: (a) administering tosaid mammal an ESA™ beta agonist having beta adrenergic activity by aclosed loop drug delivery device wherein said exercise simulating agentinduces reversible myocardial ischemia if CAD is present in said animaland is administered in an amount effective to obtain a preselected rangeof physical responses in said mammal; (b) controlling infusion of saidESA™ beta agonist into said mammal's bloodstream so as to maintain saidpreselected range of responses for a preselected time period; and (c)discontinuing infusion of said exercise simulating agent when saidpreselected time period has expired or when said physical responses areoutside said preselected range. Preferred ESA™ beta agonists includecompounds of formula I, especially preferred are compounds of StructureII. Two particularly preferred ESA™ beta agonists for diagnosticapplications such as the ESA™ beta agonist test described above arethose whose preparations are described in Examples 1 and 2 and aretermed "ESA™ beta agonist-I" and "ESA™ ##STR1## X₁ and X₂ areindependently hydrogen, hydroxy, methoxy or carbamoyl, provided that X₁and X₂ are not both hydrogen or carbamoyl; one of Y₁ and Y₂ is hydrogenand the other is hydrogen or methyl, provided that if Y₁ is methyl, thenX₁ is not carbamoyl; Z is hydrogen or hydroxy; and n is 2 or 3; or apharmaceutically acceptable acid addition salt thereof.

More preferred are ESA™ beta agonists of the above Structure I wherein Zis hydroxy ("Structure II"). Accordingly, the present invention is alsodirected to the novel ESA™ beta agonist compounds of Structure II whichare more effective at raising heart rate than dobutamine, more potent(on both a molar and a mg/kg basis) than previously known to agents suchas KM-13 and dobutamine, and, unlike KM-13 and dobutamine are suitablefor administration by non-invasive means such as transdermaliontophoresis. Particularly preferred for diagnostic uses are compoundsof Structure II where X₁ is hydrogen, X₂ is hydroxy or methoxy, and Y₁and Y₂ are hydrogen. Preferred are the R-enantiomers and racemicmixtures having the R- and S-enantiomers; of these, the R-enantiomersare most preferred.

According to one aspect of the present invention, there is provided amethod of eliciting in a mammal immediate cardiovascular responsessimilar to those cardiovascular responses elicited by aerobic exercisewhich comprises: (a) administering an exercise simulating agent (ESA™beta agonist) to said mammal by a closed loop drug delivery device; (b)controlling infusion of said exercise simulating agent into the

The term "open loop" refers to drug delivery systems in which drug isdelivered at a predetermined rate without any direct or automaticadjustment in response to physiological variables.

The closed-loop drug delivery system comprises a system capable ofadministering precise amounts of drug (ESA™ beta agonist) to the patientso that a desired response level may be maintained or, optionally,increased or decreased. Suitable drug delivery systems includetransdermal iontophoretic delivery devices and intravenous deliverydevices. The administration of drug by the device may be pulsatile orconstant rate. By using pulsatile delivery, it may be possible todeliver less total drug and yet get the same response than with constantdelivery of drug.

The closed-loop drug delivery system may include automated bloodpressure and electrocardiography devices to allow continuous monitoringof the patient's blood pressure and heart rate during the ESA™ betaagonist exercise test procedure. By monitoring the patient's response tothe ESA™ beta agonist, administration of the dose of ESA™ beta agonistmay be feedback controlled so that a desired response range is obtained.Moreover, such continuous monitoring of the patient's heart rate andblood pressure, by incorporating various "fail safe" parameters, allowsthe system to discontinue delivery of the ESA™ beta agonist to thepatient or to prevent further cardiovascular activity in response to theESA™ beta agonist. Thus, the system of the present invention wouldprovide added control and safety to the patient not available duringconventional exercise stress testing. beta agonist-II" respectively.ESA™ beta agonist-I and ESA™ beta agonist-II exhibit a combination ofadvantageously high potency and short half-life in the body, making themparticularly suitable for use as diagnostic agents. Optionally, infusionof ESA™ beta agonist may be controlled by a power source operativelyconnected to the mammal which is regulated by a microprocessor connectedto both the power source and to an electrocardiographic monitoringdevice connected to the mammal whereby infusion of said ESA™ betaagonist is feedback controlled by the microprocessor in response tochanges in heart rate.

Optionally, the ESA™ beta agonist test method may include, upondiscontinuing infusion of the ESA™ beta agonist, simultaneouslyadministering an antagonizing agent having beta adrenergic blockingactivity in an amount effective to counteract the physical responseselicited by the ESA™ beta agonist.

Optionally, the ESA™ beta agonist test method may include the additionalfeature that the flow of electrical current from the power source isdiscontinued when non-sinus or premature beats of a preprogrammed originare electrocardiographically detected. Another optional feature of theESA™ beta agonist test method is that directional flow of electricalcurrent from the power source is reversed upon the occurrence of anevent (such as maximal heart rate) preprogrammed in the microprocessor.

The term "closed loop" refers to drug delivery systems in which drug isdelivered in automatic response to feedback of a physical signal (orresponse) which could include responses such as heart rate, bloodpressure, ECG, heart output or other similar physical response.

Due to the above-noted features of the closed loop system of the presentinvention which include (a) automatic feedback control of theadministration of the ESA™ beta agonists; (b) suitability for use in thediagnosis of CAD for patients heretofore unable to use exercise stresstesting; and (c) incorporation of the above-noted "fail-safe"parameters; the method of the present invention provides a truly safeand efficient system for the diagnosis and treatment of CAD. Manynon-conditioned patients do not feel well after an exercise stress test,since they are not accustomed to strenuous physical activity. Suchnon-conditioned patients who would undergo an ESA™ beta agonist testaccording to the present invention would not have the adverse musculareffects and exhausted feeling that are often after effects of anexercise stress test.

The ESA™ beta agonist test methods of the present invention may be usedin conjunction with other diagnostic tools in order to obtain additionalinformation about a patient's cardiovascular condition. For example, useof the ESA™ beta agonist test in conjunction with diagnostic tools suchas echocardiography and radionucleotide imaging would expand theusefulness of those techniques. In the past, exercise echocardiographyhas been impractical due to technical limitations with the equipmentinvolved which were related to the difficulty of monitoring a movingpatient with rapidly expanding lungs and tachycardia. Accordingly, dueto its ability to simulate the cardiovascular effects of aerobicexercise without bodily motion, use of the test method of the presentinvention in conjunction with echocardiography may result in a simulatedexercise echocardiography which is clinically practicle. The ESA™ betaagonist test method may also be used in conjunction with radionucleotideimaging using isotopes such as Thallium 201. Since radionucleotideimaging has typically required adequate exercise levels for optimumresults, its usefulness for patients unable to exercise adequately or toachieve a maximal heart rate has been severely limited. Use of thosetechniques in conjunction with the ESA™ beta agonist test method willallow application to clinical situations previously consideredunsuitable due to the inability of the patient to exercise or achievemaximal heart rate.

Another aspect of the present invention provides a method of elicitingadaptive cardiovascular and metabolic responses similar to the adaptiveand metabolic responses elicited by aerobic activity. One embodimentcomprises administration of an ESA™ beta agonist described herein to apatient for a period of from 0.5 to 4.0 hours daily for a period of from1 to 30 days. This may be accomplished either with or without theiontophoretic delivery device described herein.

A further aspect of the present invention provides a method forincreasing cardiac contractility in a mammal having depressed cardiaccontractility by administering an effective amount of an ESA™ betaagonist of Structure II. One preferred ESA™ beta agonist is that whosepreparation is described in Example 3 herein and which is called "ESA™beta agonist-III".

The present invention also provides a method of causing adaptive effectsin a mammal similar to the adaptive effects caused by aerobic exerciseover time which comprises administering an effective amount of an ESA™beta agonist of Structure II. Particularly preferred are ESA™ betaagonist-I, -II and -III. Due to its longer half-life in the body andenhanced potency, ESA™ beta agonist-III is particularly suitable forsuch therapeutic uses.

In an additional aspect, the present invention provides a device foreliciting cardiovascular responses similar to cardiovascular responseselicited by aerobic exercise ("ESA™ beta agonist device") whichcomprises: (a) closed loop drug delivery system for administering anESA™ beta agonist into the mammal's bloodstream; (b) infusion controlsystem for controlling infusion of the ESA™ beta agonist into thebloodstream which is operatively connected to the drug delivery system;and (c) monitoring system connected to the mammal to measure a range ofresponses of the mammal to the ESA™ beta agonist which is operativelyconnected to both the drug delivery system and infusion control systemsuch that infusion of ESA™ beta agonist may be controlled to obtain andmaintain a preselected range of responses to the ESA™ beta agonist.Optionally, the device may include discontinuing system fordiscontinuing infusion of ESA™ beta agonist when a preselected timeperiod has expired or when the responses are outside the preselectedresponse range which is connected to the drug delivery system andinfusion control system. In the ESA™ beta agonist device, amicroprocessor may be used to regulate the drug delivery system,infusion control system and monitoring system (as well as the optionaldiscontinuing system), and thereby control infusion of ESA™ beta agonistin response to the measured cardiovascular responses in order to obtainthe desired preselected response range. Such ESA™ beta agonist devicesmay optionally include a second drug delivery system for administering abeta adrenergic blocking agent which is connected to the discontinuingsystem and which is activated simultaneously with the discontinuingsystem. Such ESA™ beta agonist devices may also optionally includetermination system for terminating absorption of the ESA™ beta agonistinto the bloodstream upon activation of the discontinuing system.Suitable termination system include an air-activated tourniquet oroccluder cuff.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram of a closed-loop transdermal iontophoreticdelivery system.

FIG. 2 is a logic diagram for the microprocessor software included inthe closed-loop transdermal iontophoretic delivery system.

DETAILED DESCRIPTION OF THE INVENTION

Although the method of exercise simulation using closed loop drugdelivery of the present invention encompasses the use of various closedloop drug delivery systems including intravenous administration;however, due to its non-invasive nature and concomitant advantages,transdermal iontophoretic delivery is preferred.

In one embodiment of the system of the present invention, precisequantative amounts of a drug can be delivered to the patient by closedloop iontophoretic delivery, and because the amount of drug delivered iscontrolled by the amount of electrical current needed to move the drugthrough the skin, delivery of the drug can be readily terminated byeither stopping or reversing the supply of current to the electrodes.

Such a closed-loop iontophoretic delivery system of the presentinvention may utilize microprocessor circuitry to automaticallycompensate for differences in factors such as skin impedance betweenpatients or even electrode placement on the same patient, or dosages ofan ESA™ beta agonist necessary to achieve the same cardiac responsebetween different patients. This system, by continuously monitoring thecardiovascular effects of the ESA™ beta agonist via anelectrocardiograph, processing the information to determine whether toincrease or to decrease ESA™ beta agonist administration (and thereforeheart rate), and then adjusting the amount of current supplied and hencethe amount of ESA™ beta agonist delivered, can efficiently andeffectively control the effects of the ESA™ beta agonist. Such aclosed-loop system can safely regulate the amount of ESA™ beta agonistdelivered to the bloodstream of the patient and, thus, allow apredetermined cardiac response to be achieved. Iontophoretic current orelectrode impedance can also be monitored.

The transdermal iontophoretic drug delivery device comprises a drugdelivery electrode which contains the ESA™ beta agonist and anindifferent electrode which does not contain the ESA™ beta agonist andwhich functions to close the electrical circuit.

The drug delivery electrode for the transdermal iontophoretic deliverydevice may be constructed according to one of various designs which areknown in the art (31, 32, 33, 34, 35, 36, 37, 38, 39, 40). Generally,three types of electrode pads are suitable for use as the drug deliveryelectrode in the method of the present invention, these being classifiedas: (1) monolithic pad: (2) reservoir pad: and (3) multilayer pad.Preferred are the monolithic pad and the reservoir pad.

A monolithic electrode pad design provides for including the ESA™ betaagonist in a polymer that is attached to the electrode. The polymer canalso contain an adhesive to maintain contact with the patient's skin.The ESA™ beta agonist is dispersed in the polymer during manufacture;this material is then formed into the pad itself. An example of a classof polymers suitable for use in such a pad are hydrogels. Preferredhydrogels include poly(hydroxy ethyl methacrylate) (HEMA).

A reservoir electrode pad design allows for addition of the ESA™ betaagonist drug to an electrode which comprises a disk which is attached tothe patient's skin. In such a design, the ESA™ beta agonist is containedin a reservoir or cavity in the electrode itself. The reservoir orcavity is formed during the manufacture of the electrode. The ESA™ betaagonist can be added in gel form during manufacture of the pad, afterits manufacture, or immediately prior to use.

A multilayer electrode pad includes separate layers for a bufferingsolution, an ion-exchange membrane and a drug reservoir.

Regardless of the design type of the drug delivery electrode pad, thepad itself may be of any shape, but it should conform to the area of thebody where it is applied. The size of the pad may be up to about 20 cm²,but preferably is only as large as required to keep current densitybelow 0.5 mAmp/cm², since increased pad area reduces current densitywhich may be a major factor in pH change and damage to the patients'skin and build up of a drug depot. If the drug-containing matrix itselfhas no buffering capacity, the electrode material should comprise amaterial that undergoes an oxidation reduction reaction. Suitablematerials include silver/silver chloride or zinc/zinc chlorideelectrodes; otherwise a carbon-filled electrode may be used.

The gel may comprise a soluble polyHEMA (hydroxyethylmethacrylate) [BenzResearch], hydroxypropylmethyl cellulose [Methocel, ElOM, Dow Chemical]or Carbopol [934P, BF Goodrich] and may include a preservative toprevent microbial growth; parabens, such as methyl, ethyl and propyl,are preferred preservatives. Small amounts of EDTA as a chelating agentmay be included. Preferred gels also include an antioxidant to preventoxidation due to the drug-electrode interaction. Preferred anti-oxidantsinclude sodium bisulfite and vitamin C. The solvent for the gel maycomprise deionized, pyrogen-free water or polyethylene glycol (PEG 400,10-20%). If desired, ethanol (100%) may be added as a cosolvent. Theconcentration of the drug within the gel is preferably in the range ofapproximately 5-25 mg/ml gel. It may be desirable to add a small amountof buffer (e.g. citrate, phosphate buffer) to maintain the pH in theelectrode.

Prior to placing the drug delivery electrode pad on the skin of thepatient, it may be desirable for the technician or doctor to abrade theskin using a clinically acceptable tape material or other method. Thisremoves part of the stratum corneum which is the main barrier totransport of the drug through the skin. Permeation enhancers may beapplied topically prior to applying the drug delivery electrode pad toincrease the flow of the drug through the skin; preferred permeationenhancers include surfactants such as sodium lauryl sulfate.

Similarly, the indifferent (or return) electrode may be of one of any ofthe same constructions as the drug delivery electrode except that itcontains no ESA™ beta agonist. Since hydroxyl ions may be generated atthe site of the indifferent electrode, in order to increase patienttolerance and comfort, and to decrease the occurrence of chemical burnson the patient's skin, it may be preferred for the indifferent electrodeto be buffered in order to neutralize ions generated at the electrodesite, and to decrease the occurrence of pH elevation.

A typical ESA™ beta agonist test may include several phases: (a) apre-ESA™ beta agonist monitoring phase; (b) an ESA™ beta agonistdelivery phase; and (c) a post-ESA™ beta agonist monitoring phase. Inthe pre-ESA™ beta agonist monitoring phase, a patient's physicalresponses are monitored for a period of time prior to beginningadministration of the ESA™ beta agonist This phase allows baselinevalues for physical responses (such as blood pressure, heart rate, etc.)to be established and allows the patient to become accustomed to thetest equipment. Duration of the pre-ESA™ beta agonist monitoring phaseis generally at least about ten minutes or longer if additional time isrequired to establish suitable baseline values. During the ESA™ betaagonist delivery phase, ESA™ beta agonist is administered to the patientaccording to the administration protocol selected. Administrationprotocols include ramp protocols, where the ESA™ beta agonist is at arate to give a continuous, basically linear increase in response (suchas heart rate) over time or a step protocol where response is increasedin discrete increments and then held at that increased level for aperiod of time before the next incremental increase. The drug deliveryphase lasts until a predetermined point is reached, such as maximumrecommended heart rate or an elapsed time period; or it may be endedbefore completion, for example, if physical responses go beyond apreselected range of response or if an arrythmia occurs. During thepost-ESA™ beta agonist phase, the patient is monitored until responsevalues approach the baseline value or until a second predeterminedresponse range (such as heart rate below 100) is reached.

Accordingly, in one aspect, the present invention monitors physiologicalvariables (e.g. heart rate, blood pressure, arrythmia, ischemia, e.g. STsegment deviation) and determines and automatically regulates theadministration of ESA™ beta agonists, by means of a closed-loop deliverysystem consisting of a microprocessor and software operatively connectedto a physiological monitoring sensor and a iontophoretic deliverydevice, said physiological monitoring sensor and iontophoretic deliverydevice attached to a patient as disclosed in FIG. 1. Referring to FIG.1, the microprocessor (1) controls the rate of current supplied from thesignal driver controller (4), and hence the amount of drug deliveredfrom the drug reservoir located within one of the electrodes (3a) (theother electrode being the indifferent electrode (3b)), to the patientthrough the transdermal iontophoretic delivery device (3). The amount ofcurrent supplied is a function of patient-specific data programmed intothe microprocessor by the physician (indicated generally as userinterface (5) in FIG. 1) and the response of the patient to the drug, oras a function of the feedback data obtained from the physiologicalmonitoring sensor (2) as predicated upon the particular needs orphysical characteristics of a patient relative to the effect of the ESA™beta agonist upon the patient. For example, the physician may desire acustomized protocol whereby the heart of the patient maintains asustained heart rate of 110 for 3 minutes followed by a heart rate of120 for 2 minutes, in order to create various levels of stress upon theheart. The specific heart rate and corresponding time thereof can beselected by the physician; the software can be programmed to signal thephysician when a predetermined maximum heart rate is approaching.Alternately, the physician may select from a menu any one of severalpreprogrammed fixed protocols (slow HR rise, moderate HR rise, fast HRrise, etc.) which might be most appropriate for the specific patient.The selected preprogrammed fixed protocol can then be adjusted (ifnecessary) for the desired maximum heart rate manually by the physicianor automatically by the microprocessor.

Additionally, during actual execution of either physician-selected fixedprotocols or physician-customized protocols, the system operator mayoptionally select to HOLD stable at a plateau of a specific HR (not atthe maximum heart rate) for a short period of time (potentially severalminutes) to enable diagnostic procedures to take place. In this HOLDmodality the original protocol is temporarily suspended by themicroprocessor and a fixed heart rate maintained (by the closed loopcontrol of administration of the ESA™ beta agonist drug) for thephysician's desired time duration. When the HOLD modality is completed(manually indicated by the physician or automatically indicated by themicroprocessor) the original protocol may be resumed from the point ofsuspension or terminated (manually selected by the physician orautomatically selected by the microprocessor).

Differences in skin resistivity between patients or even differentelectrode positions on the same patient can affect the amount of currentneeded to deliver a given amount of drug iontophoretically. In addition,different patients may also require a different dosage of an ESA™ betaagonist to achieve the same cardiac response. The present closed-loopsystem automatically compensates for these differences by continuouslymonitoring the cardiovascular effect of an ESA™ beta agonist on aparticular patient by way of the sensor, and adjusting the amount ofcurrent supplied to the iontophoretic delivery device, and therefore theamount of ESA™ beta agonist delivered to the patient, will be controlledby the feedback data obtained from the patient's physiological changesor from predetermined data entered into the microprocessor by aphysician in accordance with the needs of a particular patient.

In order to monitor the response of the patient to the ESA™ beta agonistand to ensure his safety, an ECG (heart rate) monitoring device (2a) anda blood pressure monitoring device (2b) are provided to monitor thepatient's heart rate and blood pressure. These variables may beprominently displayed on a display screen by the microprocessor. Thepermeability of the patient's skin for a specific ESA™ beta agonist,based on skin impedance, can be predetermined and programmed into themicroprocessor. Additionally, specific parameters, such as the patient'sage, height, weight, sex and other necessary data may be programmed intothe microprocessor.

FIG. 2 depicts a logic diagram for a software program which may be usedaccording to one embodiment of the present invention. Using the inputvariables and the sensor variables, the current necessary to deliver theESA™ beta agonist to the patient through the iontophoretic device iscalculated; these variables are monitored and are used in thecalculation of the ESA™ beta agonist dose and rate of increase ordecrease of ESA™ beta agonist dose during the course of the study.Following data entry, the key parameters (e.g. blood pressure, heartrate, impedance, and current/dose----mAmp/mMole) are displayed and alarmsignals are set which indicate when a specific pre-set level has beenachieved. Software within the microprocessor processes the data obtainedfrom the sensor connected to the patient, and based upon thosedata----as well as the achieving of a selected target heart rate, or theoccurrence of some event wherein the physician or patient desires toterminate the delivery of the ESA™ beta agonist----the control softwaresignals the signal driver controller (4) to either increase, decrease,terminate or reverse the flow of current, and thus the administration ofESA™ beta agonist.

Current is monitored as another indication of proper functioning of thesystem, since if too great a deviation from a setpoint current ismeasured, a problem may have occurred. The control software processesvarious feedback data obtained from the sensors and functions inincreasing, decreasing, terminating or reversing the flow of current tothe transdermal iontophoretic delivery device; thus, the amount of ESA™beta agonist released from the drug reservoir reflects the processing ofsuch information by the control software. During the study, the entireelectrocardiogram tracing can be recorded; electronic storage media cancontain the entire study for a specific patient. The information canalso be printed on hardcopy by way of a printer attached to themicroprocessor. Both serve as permanent records for the patient study.

Once the drug delivery electrode and indifferent electrode are attachedto the patient and current flow begins, so that the ESA™ beta agonistbegins to affect the patients' heart rate, the blood pressure and heartrate sensors provide the microprocessor and control software withinformation so that the current to the iontophoretic device (drugdelivery electrode) may be increased or decreased as required toincrease or decrease the amount of drug necessary to obtain the desiredresponse (such as heart rate) in the patient.

As indicated in FIG. 1, an ECG amplifier (6), may be connected to theECG electrodes, to amplify the signal therefrom, which signal ismonitored by an R-wave detector (7), which provides the signal drivercontroller (4) with information on the heart rate of the patient. If theheart rate or blood pressure go beyond a pre-programmed range, or ifarrythmia develops, the control software may terminate the flow ofcurrent to the iontophoretic device which will immediately terminatedelivery of the ESA™ beta agonist to the patient. Once maximal heartrate is achieved, the flow of current is also automatically terminated.If ischemia is detected, the current flow may be manually orautomatically terminated.

The preferred ESA™ beta agonists used in the method of the presentinvention advantageously have half-lifes in the bloodstream of a patientof minimal duration. However, an added safety feature may be providedwhich comprises an optional air-activated tourniquet (8), which can beapplied to the patients' body between the iontophoretic device and theheart and which will be manually or automatically activated if heartrate or blood pressure go beyond a pre-programmed range or thedevelopment of arrythmia occurs. This feature allows any residual drugto be degraded by ubiquitous enzymes and/or slowly metered into thesystemic circulation. Optionally, the microprocessor may be programmedto reverse such flow of current to the iontophoretic device upon theoccurrence of the above-noted conditions which would prevent the ESA™beta agonist from entering the bloodstream, as an added safety feature.Reversal of the flow of current would also reverse formation of any drugdepot that may develop. Optionally, the method of the present inventionmay further include co-delivery of an antagonist to the ESA™ betaagonist, for example, a beta-adrenergic blocker such as propanolol oresmolol, when reversal of the patient's response to the ESA™ betaagonist is desired to more quickly reverse the effects of the ESA™ betaagonist on the patient's system.

In another embodiment of the present invention, the closed loop drugdelivery device comprises an intravenous ("IV") delivery device.Suitable IV delivery devices include computer controlled IV infusionpumps which may be controlled by a microprocessor in much the samemanner as are the above-described transdermal iontophoretic deliverydevices. Suitable IV devices include peristaltic-type, cassette-type,syringe-type, or drop-type apparatus, or any other IV fluid deliverydevice, and includes devices such as those available from HarvardApparatus or from IVAC Corp.

Novel ESA™ Beta Agonist Compounds

In one aspect, the present invention is directed to novel ESA™ betaagonist compounds of the following structure: ##STR2## wherein X₁ and X₂are independently hydrogen, hydroxy, methoxy or carbamoyl, provided thatX₁ and X₂ are not both hydrogen or carbamoyl; one of Y₁ and Y₂ ishydrogen and the other is hydrogen or methyl, provided that if Y₁ ismethyl, then X₁ is not carbamoyl; and n is 2 or 3; or a pharmaceuticallyacceptable acid addition salt thereof. More preferred are compoundswherein Y₂ is hydrogen. Especially preferred are compounds wherein X₁ ishydrogen.

In particular, due to their advantageous combination of improvedpotency, on both a molar and a mg/kg basis, compared with agents such asKM-13 and dobutamine, and advantageous half-life in the body, havingboth an advantageously short onset and cessation of response, thefollowing compounds are especially preferred for use as diagnosticagents according to the present invention: ##STR3## In particular, ESA™beta agonist-I is about 100 times more potent than dobutamine and about15 times more potent than KM-13 on a molar basis.

Other novel ESA™ beta agonists of the present invention are particularlysuited for use as therapeutic agents due to their advantageous potencycoupled with a longer duration of activity. For example, they would beuseful as agents for eliciting adaptive cardiovascular and metabolicresponses similar to the adaptive and metabolic responses elicited byaerobic activity. One such preferred therapeutic ESA™ beta agonistcomprises the compound of the following formula: ##STR4##

The novel ESA™ beta agonist compounds of the present invention may beused as therapeutic agents to take advantage of their therapeuticeffects. These effects may be grouped into two general categories: (a)acute and (b) adaptive.

The acute effects refer to the increase of cardiac contractility thatoccurs while the ESA™ beta agonist is being administered.

The adaptive effects are those cardiovascular and metabolic responses ofthe animal provoked by repeated exposure of the animal to the ESA™ betaagonist. These adaptive responses be used to decrease body fat withoutlosing lean tissue (e.g., muscle) and, thus, could be used in thetreatment of obesity and as a means of maintaining and improvingexercise tolerance in geriatrics.

These novel ESA™ beta agonists may be conveniently administered by avariety of routes. Suitable routes of administration include buccal,oral, transdermal passive and transdermal iontophoretic. In particular,ESA™ beta agonist-III offers advantages over dobutamine as a therapeuticagent in that it is more than 300 times as potent as dobutamine, andexhibits similar effects to dobutamine but does not have to beadministered parenterally.

Due to their potency, the ESA™ beta agonist compounds of the presentinvention (of which ESA™ beta agonist-I, -II and -III are exemplary) areparticularly suited for administration by transdermal iontophoresis. Asnoted previously, transdermal iontophoresis offers a non-invasive systemfor the delivery of diagnostic and therapeutic agents, offering reducedtrauma and risk of infection. The latter characteristic has increaseddesirability due to fears generated by the risk of diseases from IV orsubcutaneous injections. However, to be suitable for iontophoreticdelivery, the diagnostic or therapeutic agent must have sufficientpotency so that an effective dose ma be administered at a current leveltolerated by the patient. Without use of a buffer in the electrode, useof currents on the order of 1 mAmp/cm² for an hour will produce achemical burn. Use of substantial buffer in the drug delivery electrodenot only will additionally increase the current required to deliver aneffective dose, but may inactivate the agent. Generally, current occurover a time period of weeks. These adaptive responses are similar tothose that occur over a time period in response to exercise trainingover weeks. One principal adaptive response is an increase in theanimal's aerobic capacity which improves its exercise tolerance.

Due to their acute effects, these ESA™ beta agonist would be useful inrelieving the symptoms of congestive heart failure.

Due to their adaptive effects, that is, their ability to elicitresponses as in exercise training, these ESA™ beta agonist would beuseful in a variety of indications. These ESA™ beta agonist may be usedas a means of rehabilitating patents whose exercise tolerance has beenimpaired by disease which has forced a period of physical inactivity.Such patients may include those suffering from heart failure causedeither by CAD or primary myocardial disease. Other patients who maybenefit from such treatment include those whose exercise tolerance hasbeen impaired as a result of peripheral vascular disease, for exampleintermittent claudication. Another group of patients who would benefitfrom the adaptive effectives of these ESA™ beta agonist are those havingforced inactivity due to injury; thus, they would be useful inrehabilitating patients who have been confined to bed as a result ofinjury. These ESA™ beta agonist would also be useful in treatingpatients physically incapable of exercise such as paraplegics,quadraplegics, amputees, stroke victims and individuals with advancedarthritis. Another adaptive effect of these ESA™ beta agonist would beto increase glucose tolerance, for example, in patients with diabetes.Due to the adaptive effects of these ESA™ beta agonists, they couldlevels of up to 0.5 mAmp/cm² for 30 minutes may be tolerated withoutadverse effects such as burns. With agents of sufficient potency,currents as low as about 0.5 mA/cm² or even as low as 0.01 mA/cm² may beused. Preferred current ranges for the ESA™ beta agonists of the presentinvention are from about 0.1 mAmp/cm² to about 0.5 mAmp/cm². Due totheir lower potency, as compared with the novel ESA™ beta agonists ofstructure II, KM-13 and dobutamine require unacceptably high currents todeliver an effective dose and hence are not suitable for transdermaliontophoretic delivery.

The present invention is directed to the closed loop delivery of ESA™beta agonists to mammals for the diagnosis, evaluation and treatment ofheart disease by a closed-loop system, and includes those novel ESA™beta agonists disclosed herein, as well as derivatives and saltsthereof, as well as other ESA™ beta agonists that accomplish theobjectives of the invention. Salts include acid addition salts formedfrom organic or inorganic acids. Preferred are hydrochloride salts.Other salts include acetate, citrate, hydrogen oxalate, hydrogentartrate, hydrobromide, and hydrogen sulfate salts, as well as otherpharmaceutically acceptable salts.

The Examples that follow demonstrate preparation of some of the novelESA™ beta agonist's of the present invention (including ESA™ betaagonist-I, -II and -III) by two particular synthetic routes. However,preparation of these ESA™ beta agonist's is not limited to the routesdescribed herein. Other conventional synthetic methods known to thoseskilled in the art may be used to prepare these ESA™ beta agonistcompounds.

(a) Preparation of 4-(4-Hydroxyphenyl)butanol

To a solution of 4-(4-methoxyphenyl)butanol (100 g, 0.55 mole) indichloromethane, cooled to -75° C. in a dry ice-acetone bath, a solutionof boron tribromide (278 g; 2.0 mole) was added slowly over one hour.The cooling bath was then removed and the reaction mixture allowed towarm to 15° C. slowly. The reaction was shown to be complete by thinlayer chromatography (TLC). The reaction mixture was again cooled in anice-water bath; 10% sodium hydroxide solution was added until pH ofabout 9 was obtained. The resulting mixture was then acidified withconcentrated HCl to a pH of about 2. The organic layer was separated,the aqueous layer was extracted once with ethyl acetate. The combinedorganic layers were dried over magnesium sulfate, filtered andconcentrated to give 90 g of crude product. The crude product waspurified by dry filtration chromatography using 10% ethylacetate/dichloromethane as eluent giving an 86% yield of pure4-(4-hydroxyphenyl)butanol. The ¹ H NMR was consistent with the assignedstructure.

(b) Preparation of 4-(4-Benzyloxyyphenyl)butanol

To a solution of 4-(4-hydroxyphenyl)butanol (125 g, 0.75 mole) inacetone 0.85.8 g (1.25 mole) anhydrous potassium carbonate (285.8 g,1.25 mole) was added, followed by 160.8 (0.94 mole) benzyl bromide. Thereaction mixture was then heated at reflux for 25 hrs. After cooling toroom temperature, the reaction mixture was filtered and the filter cakewashed with acetone. The filtrate was concentrated to dryness. The solidresidue was washed twice with 500 ml hexane. After drying under

Of the two synthetic routes described, the first (See Example 2)comprises coupling a suitably protected bromoketone, such as3,4-dibenzyloxy-2'-bromoacetophenone with an amine, reducing theresulting amino ketone to the amino alcohol and removing thebenzyl-protecting groups.

The second route comprises coupling (R)-norepinphrine with a ketone oraldehyde in the presence of hydrogen and a hydrogenation catalyst, suchas a mixture of platinum and palladium catalysts, preferably platinumoxide and palladium on carbon. Use of this second route appears toenhance the yield of the desired product. Also, this route directlyallows preparation of the preferred (R)-isomer of the ESA™ beta agonist.

The following examples describe the synthesis of useful exercisestimulating agents. They are set forth for illustrative purposes onlyand are not to be construed as limiting the claims.

EXAMPLE 1 Preparation of 1-(3,4dihydroxyphenyl)-2-(4-(4-hydroxyphenyl)butylamino)ethanol hydrochloride##STR5##

The R-enantiomer is prepared by the procedures described below; someS-enantiomer may be prepared also. high vacuum overnight, 161 g of thedesired product were obtained, which was homogeneous on TLC. The ¹ H NMRspectrum was consistent with the assigned structure.

Preparation of 4-(4-Benzyloxyphenyl)butanal

To a solution of 4-(4-benzloxyphenyl)butanol (170.0 g, 0.66 mole) indichloromethane cooled in an ice-water bath, 215.0 (1.0 mole) pyridiniumchlorochromate was added in portions. After the addition was complete,the cooling bath was removed. The reaction mixture was stirredvigorously while warming to room temperature. After 3 hours, the darkbrown solution was decanted; 1.5 L of ether was added to the residue.The residue was stirred in ether for 15-30 minutes and then filtered.The organic extracts were combined and filtered through a bed ofbentonite. The clear filtrate was dried over magnesium sulfate, filteredand concentrated to afford a near quantitative yield of crude aldehyde(166 g). Purification of the crude aldehyde by dry filtrationchromatography using 3% hexane/ethyl acetate as eluent gave 134 g ofproduct. The ¹ H NMR spectrum was consistent with the assignedstructure.

(d) Preparation of1-(3,4-Dihydroxyphenyl)-2-(4-(4-hydroxyphenyl)-butylamino)ethanolhydrochloride

To a 3.8 L pressure vessel, was charged methanol containing 2% aceticacid (2.6 L) and (R)-norepinephrine (44.0 g, 0.26 mole) followed by PtO₂(5.86 g) and Pd/C (3.9(g). The mixture was then hydrogenated under 15psi for 15 minutes. The above butanal (85.9 g 0.34 mole) was added tothe mixture and hydrogenation continued at 30 psi for 24-48 hours. Thecatalysts were removed by filtration. The filtrate was concentratedunder reduced pressure to dryness. The crude product was purified byfiltration chromatography using dichloromethane/methanol/acetic acid(10:2:0.1) as eluent. The fractions containing the desired product(Rf=0.45, dichloromethane/methanol/acetic acid, 8:2:1) were pooled andconcentrated to dryness. The residue (18.0 g) was dissolved in methanol,treated with Dowex 50 X-8 resin and filtered. The filtrate was acidifiedwith concentrated HCl to a pH of about 4, concentrated to a smallvolume, and then added to anhydrous ether. The desired hydrochloridesalt precipitated from the solution, was collected and dried under highvacuum to give 13.5 g of product. Further purification of the fractionscontaining a mixture of products and Dowex-5 8X treatment gave anadditional 125 g of slightly less pure product. The first crop of saltwas further purified by dissolving in water, filtering and lyophilizing;mp 55°-58° C.; [α]_(D) (23° C.)=-18.5 (C=1.0, C₂ H₅ OH); I.R. 3500,1600, 1250 CMl; ¹ H NMR (DMSO-d₆) δ 8.95 (d,2H,OH), 8.90-8.50 (brds,2H,NH,OH), 7.00-6.60 (m, 7H, ArH), 6.95 (d,2H, CHOH), 4.75(m,1H,CHOH), 3.00-2.90 [m,4H,CH₂ N), 2.50-2.40 (m,2H,ArCH), 1.70-1.50(m,4H,CH₂ CH₂).

EXAMPLE 2 Preparation of1-(3,4-dihydroxyphenyl)-2-[3-(4-methoxyphenyl)propylamino] ethanolhydrogen oxalate ##STR6## (a) Preparation ofN-Benzyl-3-(4-methoxyphenyl) propanamide

To a solution of 10.80 g (0.060 mole) of 3-(4-methoxyphenyl) propanoicacid and 6.57 g (0.065 mole of triethylamine in 25 ml dichloromethane atabout 0.5° C., 6.84 g (0.063 mole) of ethyl chloroformate was addeddropwise. The mixture was stirred for about 15 minutes at a temperatureof about 5° to 10° C., then 6.96 g (0.065 mole) of benzylamine wereadded. The resulting mixture was stirred for about thirty minutes, andthe solvent was evaporated. The residue was slurried in 5% aqueoussodium hydroxide. The solid was collected by filtration and rinsed withwater until neutral. The washing process was repeated using 5%hydrochloric acid. The residue was dried under vacuum to give 11.0 g ofthe above-identified product, melting point 92°-94° C., which wassuitable for use in step (b).

(b) Preparation of N-Benzyl-3-(4-methoxyphenyl)propylamine

To 50 ml of 1M BH₄ -THF under an argon atmosphere cooled to 0° C., asolution of 4.2 g (0.015 mole) ofN-benzyl-3-(4-methoxyphenyl)propanamide in 10 ml anhydrous THF wasadded. The reaction mixture was stirred overnight, then quenched withwater and evaporated. The residue was partitioned in ether and 5% sodiumhydroxide. The organic (ether) layer was separated, dried (over Na₂ SO₄)and evaporated. That residue was dissolved in 50 ml of 10% ethanol inether; then 2.6 ml of concentrated hydrochloric acid was added. Themixture was stirred overnight. The solid was collected by filtration,rinsed with ether, and dried to give the hydrochloride salt. The freebase was obtained by dissolving the salt in a mixture of 10% aqueouspotassium carbonate and ether. The ether extract was dried andevaporated to give the 2.8 g of the free base of the above-identifiedcompound. The ¹ H NMR was consistent with the assigned structure.

(c) Preparation of(R),(S)-1-(3,4-Dibenzyloxyphenyl)-2-[N-benzyl-3-(4-methoxyphenyl)propylamino]ethanol

To a solution of 2.04 g (9.0 mmole)N-benzyl-3-(4-methoxyphenyl)propylamine (the product of step (b)) in 20ml dimethylformamide (DMF), 1.0 g anhydious potassium carbonate wasadded. To that stirred mixture, a solution of 3.31 g (8.05 mmole) of3,4-dibenzyloxy-2'-bromoacetophenone was added dropwise. The resultingmixture was stirred overnight, then poured into water and extracted withmethylene chloride, and evaporated. The residue was dissolved in 10%dioxane in ethanol. The solution was cooled to about 0° to 5° C. withstirring, and 2.0 g of NaBH₄ were added. The resulting mixture wasstirred overnight, then evaporated and partitioned between water andether. The organic layer was dried (with Na₂ SO₄) and evaporated underreduced pressure. The residue was chromatographed on silica gel, usingchloroform:ethyl acetate. The appropriate (monitored by TLC 95:5chloroform:methanol) fractions were combined and evaporated. The residuewas crystallized from ethanol/ether to give 2.4 g of theabove-identified product, melting point 59°-62° C. The ¹ H-NMR wasconsistent with the assigned structure.

(d) Preparation of(R),(S)-1-(3,4-dihydroxyphenyl)-2-[3-(4-methoxyphenyl)propylamino]ethanolhydrogen oxalate

To a solution of 1.50 g (2.6 mmole) of the above benzyl-protected aminoalcohol (the product of step (c)) in 150 ml ethanol containing 10%dioxane, 400 mg of 10% Pd on carbon atom were added. The reactionmixture was hydrogenated overnight at 25 psi. To the resulting mixture,was solution of 0.23 g (2.60 m mole) of oxalic acid in 2 ml ethanol wasadded. After mixing, the solution was filtered and evaporated underreduced pressure. The residue was slurred in ether. The precipitate wascollected by filtration, rinsed with ether and then acetone, and driedunder vacuum to give 0.570 g of the above-identified product, meltingpoint 158°-162° C. ¹ H NMR (CD₃ OD) δ7.0-6.5 (m, 7H, ArH), 4.8 (m, 1H,CHOH), 3.3 (S, 3H, CH₃ O), 3.00-2.90 (m,4H, CHN), 2.5-2.4 (m, 2H,ArCH₂), 1.6-1.5 (m, 2H, CH₂).

EXAMPLE 3 Preparation of1-(3,4-dihydroxyphenyl)-2-[3-(4-carbamoylphenyl)-1-methylpropylamino]-ethanol acetate and hydrogen tartrate ##STR7## (a)Preparation of 4-(4-cyanophenyl)-2-butone

To a stirred solution of 80.0 g (0.4 mole) of4-(chloromethyl)benzonitrile and 60.0 g (0.60 mole) of 2,4-pentanedionein 0.5 l of ethanol, 60.7 g (0.44 mole) of potassium carbonate wasadded. The reaction mixture was then refluxed with stirring for 6 hours.The combined ether extracts were washed with water, dried (with Na₂ SO₄)and evaporated in vacuo. That residue was distilled. The fraction bpt.90°-110° C./5 mmHg was recrystallized from ether to give 42.3 g of theabove-identified product. The ¹ H NMR was consistent with the assignedstructure.

(b) Preparation of 4-(4-carbamoylphenyl)-2-butanone

To a stirred solution of 9.70 g (0.056) mole of4-(4-cyanophenyl)-2-butanone (the product of step (a)) in 15 ml ofmethanol, 1.80 g of potassium bicarbonate and 0.20 g of potassiumcarbonate were added. To the resulting mixture, 10.0 ml (0.088 mole) of30% hydrogen peroxide was added dropwise over an hour. The reactionmixture was stirred for 24 hours and then chilled. The solid wascollected by filtration, was rinsed twice with water and was dried togive 9.67 g of the above-identified product, melting point 152°-154° C.The ¹ H NMR was consistent with the assigned structure.

(c) Preparation of(R,R),(R,S)-1-(3,4-dihydroxyphenyl-2-[3-(4-carbamoylphenyl)-1-methylpropylamino]ethanolhydrogen tartrate

A solution of 3.40 g (R)-norepinephrine and 4.20 g4-(4-carbamoylphenyl)-2-butanone (the product of step (b)) in methanolcontaining 2% acetic acid, was hydrogenated over PtO₂ and Pd/C at 30 psias previously described in step (d) of Example 1. After 24 hours themixture was filtered, evaporated and chromatographed on silica with4:1:1 chloroform:ethanol:acetic acid. Fractions containing the desiredproduct, as indicated by TLC, were combined, evaporated and dried undervacuum to give the acetate salt as an oil. ¹ H NMR (CD₃ OD) δ 7.5-6.7(m,8H), 4.7 lm, 1H, CHOH), 3.3-3.0 (m, 3H, CH₂ N and CH₃ CHN), 2.8-2.5(m, 4H, CH₂ CH₂), 2.0 (brd δ, AcO), 1.35 (2d, 6H, CH₃). Integration ofmethyl doublets indicated an R,R:R,S ratio of 53:47.

The hydrogen tartrate salt was prepared by dissolving the acetate saltin methanol and then passing the resulting solution through Dowex 50 X-8resin. The filtrate was treated with an equimolar amount of tartaricacid, stirred until homogeneous, concentrated and triturated with ether.The solid was collected by filtration and dried under vacuum to give theabove-identified product, melting point 85°-90° C.

EXAMPLE 4 Preparation of1-(3,4-dihydroxyphenyl)-2-[3-(3-carbamoylphenyl)propylamino]ethanol

The compound represented by the following chemical structure: ##STR8##It was prepared according to the following procedure:

(a) Preparation of 3-(3-cyanophenyl)propanoic acid

To 200 ml of a solution of 20.0 g potassium carbonate in 250 ml water,15 g of 3-cyanocinnamic acid was added; the resulting mixture was heateduntil all the acid was in solution. The solution was cooled and filteredand rinsed with water to 250 ml total volume. Then 0.95 g of 10%palladium on carbon was added and the solution was hydrogenated at 8.5psi for two hours. The reaction mixture was filtered, and then acidifiedto a pH of about 1 by the dropwise addition of concentrated hydrochloricacid, being careful to avoid too much foaming. The mixture was chilledin an ice bath and filtered to collect the precipitated product acid.The precipitate was rinsed several times with cold water and driedovernight, to give 13 g of the above-identified product as a solid,melting point 95° C.

(b) Preparation of 3-(3-cyanophenyl)-1-propanol

Into an oven-dried 500 ml flask with 2-neck adapter and stirring bar,12.9 g of 3-(3-cyanophenyl)propanoic acid (the product of step (a)) wasplaced. The system was flushed with argon gas; then 84 mltetrahydrofuran was added. The resulting mixture was stirred until theacid was dissolved. After cooling for about ten minutes with an icebath, 88 ml boranetetrahydrofuran was added in two 44 ml portions over a20 minute period. The reaction mixture was stirred for 20 minutes in anice bath and then quenched by the addition of about 17 ml waterdropwise. The mixture was stripped to give an oil with white crystals.Ether (200 ml) and a solution of 8.8 g (0.22 mole) sodium hydroxide in150 ml water were added. The organic phase was separated. The aqueouslayer was extracted with an additional 35 ml ether. The combined etherextracts were dried over sodium sulfate, filtered, and stripped. Theresulting oil was distilled in a Kugelrohr apparatus, the fraction bpt.95°-110° C. was collected to give 11.5 g of the above-identifiedproduct.

(c) Preparation of 3-(3-bromopropyl)cyanobenzene

To a mixture of 21.8 g (0.083 moles) of triphenyl phosphine stirred in30 ml acetonitrile, 13.2 g (4.26 ml) bromide in 75 ml acetonitrile wasadded dropwise with stirring in an ice bath. After the addition wascomplete, the ice bath was removed and the mixture warmed to roomtemperature. Then a mixture of 12.1 g (0.075 mole) of3-(3-cyanophenyl)-1-propanol (the product of step (b)) in 30 mlacetonitrile was added dropwise. The resulting mixture was allowed towarm to about 45°-50° C., was stirred overnight and then stripped.Benzene (50 ml) was added to the residue; the mixture was evaporated.Then, additional benzene (50 ml) was added. The mixture was stirred, andthen filtered to remove the triphenyl phosphine. The filtrate wasstripped to give an oil. The oil was chromatographed using a columncontaining 3.5 inches of 200 mesh silica gel (Merck) eluting withbenzene, until TLC showed that no further product was eluted from thecolumn. The eluates were pooled and stripped to give 17 g of an oil. Theoil was distilled in a Kugelrohr apparatus, the fraction bpt. 102°-103°C. was collected to give 15.7 g of the above-identified product as anoil.

(d) Preparation of 3-(3-bromopropyl)benzamide

To 15.2 g (0.067 mole) of 3-(3-bromopropyl)cyanobenzene (the product ofstep (c)) in 55 ml methanol, 2.2 g potassium bicarbonate was added; tothat mixture, 15.2 ml of 30% hydrogen peroxide was added dropwise. Thereaction mixture was stirred for about 45 minutes. Then, 113 mgpotassium carbonate was added the resulting mixture was stirredovernight. Water (about 35 ml) was added to the reaction mixture and theresulting solution put in a freezer for about 50 minutes. The solid wascollected by filtration and dried overnight to give 15.9 g of theabove-identified product as a solid, melting point 109° C.

(e) Preparation of N-3-(3-carbamoylphenyl)propyl]phthalimide

A mixture of 14.0 g (0.057 mole) 3-(3-bromopropyl)benzamide (the productof step (d)), 11.5 g potassium phthalimide and 26.3 ml dimethylformamidewas heated to reflux under argon gas for four hours. The heat source wasremoved and the mixture was stirred to cool to room temperature. Water(about 85 ml) was added. The resulting slurry was stirred for 20minutes, then filtered and washed three times with about 50 ml coldwater (each wash made a slurry solution in the funnel). The solids werethen washed with about 20 ml cold 1:1 isopropyl alcohol: water and driedunder vacuum overnight to give 17.04 g of the above-identified product.

(f) Preparation of 3-(3-aminopropyl)benzamide

A mixture of 15.42 g (0.05 mole)N-[3-(3-carbamoylphenyl)propyl]phthalimide (the product of step (e)),2.76 g (0.055 mole) hydrazine monohydrate and 100 ml ethanol wasrefluxed for about four hours under argon with heat, and then allowed tostir overnight. The reaction mixture was acidified with 30% (v/v)hydrochloric acid to a pH of about 1. Additional ethanol (about 10 to 20ml) was added to the thick mixture. The mixture was filtered; the solidswere rinsed with ethanol. The filtrate was evaporated to give a solid.Water (about 15 ml) was added to the solid; the resulting mixture wasfiltered. The filtrate wa basified with dry potassium carbonate untilsaturated, then extracted three times with 20 ml butanol. The butanolextracts were dried over sodium sulfate and potassium carbonateovernight, filtered and stripped to give 4.25 g of the above-identifiedproduct.

(g) Preparation of 3-3-(benzylamino)propyl]benzamide hydrogen oxalate

To a mixture of 4.25 g (0.023 mole) 3-(B-aminopropyl)benzamide (theproduct of step (f)) in 55 ml ethanol, 2.79 g (2.67 ml) benzaldehyde wasadded. The resulting mixture was refluxed for one hour, cooled to roomtemperature and then filtered. The filtrate was transferred to a Parrbottle containing 222 mg of platinum/carbon 10% (5 ml ethanol was addedto wet the catalyst) rinsed with ethanol to a total volume of about 80ml. After bubbling argon through the solution, it was placed on the Parrat overnight at about 30 psi hydrogen. The mixture was filtered and thesolids rinsed with ethanol. The filtrate was stripped to give an oil.

The oil was redissolved in 30 ml ethanol, to that solution 2.14 g oxalicacid in 13 ml ethanol was added dropwise with stirring. The whiteprecipitate that formed was stirred for 25 minutes, then cooled for 25minutes, filtered to collect the white solids. The solids were slurriedwith 8 ml cold ethanol and 14 ml acetone, and then dried to give 6.9 gof the above-identified product.

(h) Preparation of 3-[3-(benzylamino)propyl]benzamide (free base)

To 6.7 g (0.0187 mole) of 3-[3-(benzylamino)propyl]benzamide oxalate(the product of step (g)) slurried in 20 ml water, 7.7 g (0.056 mole)potassium carbonate (and 700 mg potassium hydroxide) in 50 ml ethylacetate was stirred until all solids were dissolved. The aqueous andethyl acetate phases were separated. The aqueous layer was washed withabout 30 ml ethyl acetate. The ethyl acetate extracts were combined,washed over saturated saline and dried over sodium sulfate, filtered.The filtrate was dried to an oil on a vacuum pump overnight to give 4.9g of the above-identified product.

(i) Preparation of1-(3,4-dibenzyloxyphenyl)-2-[N-benzyl-3-(3-carbamoylphenyl)propylamine]ethanol

To a mixture of 5.00 g (0.018 mole) 3-[3-(benzylamino)propyl]benzamide(the product of step (h)) in 50 ml dimethylformamide (DMF), 3.75 g(0.027 mole) potassium carbonate was added, followed by a dropwiseaddition of 8.13 g (0.019 mole) 3,4-dibenzyloxy-2'-bromoacetophenone.The reaction mixture was stirred overnight; a drying tube was used.After being stirred for about 20 hours, the reaction mixture was pouredinto 375 ml water in a 1000 ml separatory funnel. The mixture wasextracted three times with chloroform (60 ml, 30 ml and 20 mlrespectively). The chloroform extracts were back-washed with a saturatedsodium chloride solution, dried over sodium sulfate, and filtered. Thefiltrate was stripped and pumped under vacuum to give an oil.

The oil was dissolved in 300 ml absolute ethanol. To that mixture, 2.5 g(0.065 mole) sodium borohydride was added; the resulting mixture wasstirred overnight (a drying tube was used). The reaction mixture wasfiltered; the solids were washed with ethanol. The solids were slurriedin about 35 to 40 ml absolute ethanol. The slurry was stirred for about30 minutes in a warm water bath, then cooled in a refrigerator, andfiltered. The solids were washed with absolute ethanol and dried under avacuum pump overnight to give 7.0 g of the above-identified product as asolid, melting point 131° C.

(j) Preparation of1-(3,4-dihydroxyphenyl)-2-3-(3-carbamoylphenyl)propylamino]ethanolhydrogen oxalate

A 2.0 g portion of1-(3,4-dibenzyloxyphenyl)-2-[N-benzyl-3-(3-carbamoylphenyl)propylamino]ethanol(the product of step (i)) was recrystallized according to the followingprocedure: it was dissolved in 15 ml absolute ethanol by heating, thencooled to room temperature and cooled further in a freezer. The solidswere collected by filtration, rinsed with ethanol and air dried for 30minutes. The solids were dissolved in ethyl acetate using heat. Themixture was cooled to room temperature and then cooled in a freezer forabout 30 minutes. The solids were collected by filtration and driedunder vacuum.

A 0.85 g (1.4 m mole) portion of the recrystallized1-(3,4-dibenzyloxyphenyl)-2-[N-benzyl-3-(3-carbamoylphenyl)propylamino]ethanolwas dissolved in 50 ml methanol with heat. Palladium on carbon (300 mg)was wet with 5 ml methanol in a Parr bottle. The methanol solution wasadded and rinsed with an additional 10 ml methanol. The mixture washydrogenated at about 21 to 22.5 psi for about 24 hours. Progress of thereaction was checked using TLC. Argon was passed through the reactionsystem (to purge the system) while TLC was run. After completion of thereaction, a solution of 126 mg (1.4 m mole) oxalic acid in about 2 mlethanol was added, and the resulting mixture was stirred for about 10minutes while passing Argon gas through the reaction mixture. Themixture was filtered and stripped; then about 10 ml methanol was added.To that solution, 10 ml ether was added dropwise (in dry ice). Themixture was put in the freezer overnight. The methanol-ether solutionwas poured out by pipetting. The solids were washed twice with 50:50methanol: ether and twice with ether; then dried under vacuum overnightto give about 310 mg of the above-identified oxalate salt.

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We claim:
 1. A transdermal iontophoretic device for closed loop deliveryof a drug to a mammal comprising:at least one cardiovascular sensingdevice being operatively connected to said mammal; said devicesimultaneously being operatively connected to a device for receiving andprocessing a signal from said sensing device; said receiving andprocessing device simultaneously being operatively connected to a powersource; said power source simultaneously being operatively connected toa transdermal iontophoretic drug delivery device; and said drug deliverydevice simultaneously being operatively connected to said mammal;wherein an air-activated tourniquet is operatively connected to saidreceiving and processing device.
 2. A transdermal iontophoretic devicefor closed loop delivery of a drug to a mammal comprising:at least onecardiovascular sensing device being operatively connected to saidmammal; said device simultaneously being operatively connected to adevice for receiving and processing a signal from said sensing device;said receiving and processing device simultaneously being operativelyconnected to a power source; said power source simultaneously beingoperatively connected to a transdermal iontophoretic drug deliverydevice; and said drug delivery device simultaneously being operativelyconnected to said mammal; wherein said drug has the chemical structure:##STR9## wherein X₁ and X₂ ar independently hydrogen, hydroxy, methoxyor carbamoyl, provided that X₁ and X₂ are not both hydrogen orcarbamoyl; one of Y₁ and Y₂ is hydrogen and the other is hydrogen ormethyl, provided that if Y₁ is methyl, then X₁ is not carbamoyl; Z ishydrogen or hydroxy; and n is 2 or 3; or a pharmaceutically acceptableacid addition salt thereof.
 3. The drug delivery device of claim 2wherein X₁ is hydrogen, X₂ is hydroxy, Y₁ and Y₂ are hydrogen, Z ishydroxy and n is
 3. 4. The drug delivery device of claim 2 wherein X₁ ishydrogen, X₂ is methoxy, Y₁ and Y₂ are hydrogen, Z is hydroxy and n is2.
 5. A closed loop transdermal iontophoretic delivery system forcontrolling the delivery of a drug to a mammal comprising:means formonitoring at least one cardiovascular variable of said mammal, andmeans for producing a signal from said monitoring means; means forreceiving and processing said signal; and means for controlling deliveryof a drug to said mammal through a transdermal iontophoretic deliverydevice in response to said signal, wherein said drug is an ionizedcatecholamine and wherein said drug has the chemical structure:##STR10## wherein X₁ and X₂ ar independently hydrogen, hydroxy, methoxyor carbamoyl, provided that X₁ and X₂ are not both hydrogen orcarbamoyl; one of Y₁ and Y₂ is hydrogen and the other is hydrogen ormethyl, provided that if Y₁ is methyl, then X₁ is not carbamoyl; Z ishydrogen or hydroxy; and n is 2 or 3; or a pharmaceutically acceptableacid addition salt thereof.
 6. The system of claim 5 wherein X₁ ishydrogen, X₂ is hydroxy, Y₁ and Y₂ are hydrogen, Z is hydroxy and n is3.
 7. The system of claim 5 wherein X₁ is hydrogen, X₂ is methoxy Y₁ andY₂ are hydrogen, Z is hydroxy and n is
 2. 8. A closed loop transdermaliontophoretic delivery system for controlling the delivery of a drug toa mammal comprising:means for monitoring at least one cardiovascularvariable of said mammal, and means for producing a signal from saidmonitoring means; means for receiving and processing said signal; meansfor controlling delivery of a drug to said mammal through a transdermaliontophoretic delivery device in response to said signal; and an airactivated tourniquet operatively connected to said receiving andprocessing means and said mammal.
 9. A device for elicitingcardiovascular responses in a mammal similar to cardiovascular responseselicited by aerobic exercise which comprises:(a) a drug delivery systemfor administering an exercise simulating agent into said mammals bloodstream; (b) an infusion control system for controlling infusion of saidexercise simulating agent into the blood stream of said mammal which isoperatively connected to said delivery system, said infusion controlsystem including a discontinuing system for discontinuing infusion ofexercise simulating agent into said mammal's blood stream when apreselected time period has expired or when said cardiovascularresponses are outside said preselected range and which is operativelyconnected to said drug delivery system, said control system furtherincluding a second drug delivery system for administering a β-adrenergicblocking agent controlled by said discontinuing system which isactivated simultaneously with the discontinuing system and whichadministers said blocking agent when said discontinuing system isactivated; and (c) a monitoring system connected to said mammal tomeasure response levels of said mammal to said exercise simulating agentwhich is operatively connected to said drug delivery system and infusioncontrol system such that infusion of exercise simulating agent may befeedback-controlled to obtain and maintain a preselected range ofresponses of said mammal to said exercise simulating agent.
 10. A devicefor eliciting cardiovascular responses in a mammal similar tocardiovascular responses elicited by aerobic exercise whichcomprises:(a) a drug delivery system for administering an exercisesimulating agent into said mammal's blood stream; (b) an infusioncontrol system for controlling infusion of said exercise simulatingagent into the blood stream of said mammal which is operativelyconnected to said delivery system, said infusion control systemincluding a discontinuing system for discontinuing infusion of exercisesimulating agent into said mammal's blood stream when a preselected timeperiod has expired or when said cardiovascular responses are outsidesaid preselected range and which is operatively connected to said drugdelivery system, said control system further including an air activatedtourniquet for terminating absorption of said exercise simulating agentinto said mammal's blood stream when said discontinuing system isactivated; and (c) a monitoring system connected to said mammal tomeasure response levels of said mammal to said exercise simulating agentwhich is operatively connected to said drug delivery system and infusioncontrol system such that infusion of exercise simulating agent may befeedback-controlled to obtain and maintain a preselected range ofresponses of said mammal to said exercise simulating agent.